19 Safety of Ultrasound Contrast Agents

Safety of Ultrasound Contrast Agents 131 19 Safety of Ultrasound Contrast Agents

R. Oyen

CONTENTS approved for clinical use, and they are all based on microbubbles (Table 19.1). 19.1 Introduction 131 The effect of ultrasound contrast media is mainly 19.2 General Considerations on the Acoustic Properties of Microbubble Based Ultrasound Contrast produced by increased backscattering intensity Media 131 as compared to that from blood, other fluids, and 19.3 Experimental Findings on Microbubble Based most tissues (Jakobsen 1996). The spectral Doppler Ultrasound Contrast Media 131 intensity is also increased, with a brighter spectral 19.4 Clinical Safety of Ultrasound Contrast Media 132 waveform displayed, and a stronger sound is pro- 19.5 Recommendation on the Use of Ultrasound Contrast Media 133 duced. When color Doppler technique is applied, 19.6 Conclusion 133 ultrasound contrast media enhance the frequency References 134 or the power intensity and thus give rise to stronger color encodings. The effect of ultrasound contrast media is most efficient when various contrast spe- cific nonlinear techniques are used. Typically, the 19.1 microbubbles oscillate as a response to the external Introduction sound field during scanning, both in a linear and in a nonlinear way. This is the basis for nonlinear tech- The use of ultrasound contrast agents has increased niques such as second harmonic imaging (Burns over recent years. It is generally considered that 1996), pulse or phase inversion, or pulse cancella- ultrasound contrast agents approved for clinical use tion, which improves the detection of microbub- are well tolerated and serious adverse reactions are bles specifically (Burns et al. 2000). The effect on rarely observed. In this chapter the evidence sup- microbubble behavior is dependent on the acoustic porting this impression is reviewed. pressure created by the ultrasound probe. Usually, with increasing wave pressure, the effect on imaging comes from reflection, then asymmetrical vibration, and finally disruption of microbubbles, respectively 19.2 (Correas et al. 2001). These changes in microbub- General Considerations on the Acoustic ble behavior may induce unwanted effects. There- Properties of Microbubble Based fore, the effect of insonation on microbubble behav- Ultrasound Contrast Media ior is dependent on the level of the mechanical index (MI), as well as the properties of the contrast agent Ultrasound contrast media for intravenous injec- and the imaging mode chosen. tions are usually gas-filled microbubbles with a mean diameter less than a red blood cell. The contrast agents can be described according to the concentration of particles, size of particles or 19.3 microbubbles, volume of gas, kind of gas, kind of Experimental Findings on Microbubble shell, additives, etc. There are only a few products Based Ultrasound Contrast Media

The cavitation phenomenon refers to formation, R. Oyen, MD growth and collapse by implosion of microbubbles. Department of Radiology, Katholieke Universiteit Leuven, The “cavitation threshold” is the level at which the Herestraat 49, 3000 Leuven, Belgium amount of acoustic energy introduced into the fluid 132 R. Oyen

Table 19.1. Ultrasound contrast agents. Not all are commercially available. Generic names are given in parentheses

Product name Clinical nature Imavist (AF0150) Perfluorohexane and nitrogen gas in stabilized microbubbles SonoVue (BR1) Sulphur hexafluoride gas in polymer with phospholipids Definity (DMP 115) Fluorocarbon gas in liposomes Albunex Air-filled protein shell Optison (FS069) Octafluropropane-filled albumin microspheres Echovist Galactose-based gas bubbles Levovist (SHU 508A) Galactose-based, palmitic acid stabilized air-bubbles initiates cavitation. The implosion causes large changes 19.4 in pressure and temperature in the close vicinity. This Clinical Safety of Ultrasound Contrast Media cavitation phenomenon has caused concern in rela- tion to the safety of microbubble enhancing agents. The side effects observed in animal studies have In vitro studies have shown that ultrasound con- not been observed in clinical practice despite exten- trast agents may cause hemolysis and platelet aggre- sive investigation (Nanda and Carstensen 1997; gation (Miller and Gies 1998; Poliachick et al. Morel et al. 2000; Myreng et al. 1999; Robbin et 1999; Carstensen et al. 1993; Everbach et al. 1998). al. 1998; Borgers et al. 2002). The microbubbles are The amount of hemolysis seems to correlate with the so small that obstruction or trapping in the capil- amount of microbubbles present, the acoustic pres- laries does not seem to be a problem. Adverse reac- sure exerted on the blood, and also depends on the tions caused by cavitation have not been shown in type of ultrasound contrast medium. The phenom- humans. The galactose content of some agents, and enon of cavitation is considered to be the cause of human protein content of others have been consid- most of the observed side effects. ered to be the potential causes of adverse reactions, In vivo studies of pigs and dogs with pulmonary but clinical investigations have shown no major hypertension have shown that pulmonary function can problems so far. be affected by high doses of ultrasound contrast media The most common general adverse reactions (Walday et al. 1994; Ostensen et al. 1992; Yamaya et reported are the same as those seen with other al. 2002). The interaction between ultrasound contrast types of contrast media, i.e. headache, warm sensa- media and pulsed ultrasound waves seems not to cause tion and flushing. More unusual events are nausea pulmonary damage (Raeman et al. 1997). and vomiting, dizziness, chills and fever, altered Animal studies showed no significant effect of taste, dyspnea, chest pain, etc. (0%–5%) (Correas ultrasound contrast media on left ventricular (LV) et al. 2001; Myreng et al. 1999; Bokor et al. 2001; function or myocardial blood flow (Main et al. Claudon et al. 2000; Rott 1999; ter Haar 2002; 1997; Meza et al. 1996). However, Chen et al. (2002), Goldberg 1997; Cohen et al. 1998; Kaps et al. reported an increase in troponin T (a marker of myo- 1999; Fritsch and Schlief 1995). Similar find- cardial ischemia) when a high mechanical index for ings were however observed in placebo groups. bubble destruction was transmitted. This was not Such adverse reactions are rare, usually transient, associated with LV dysfunction or histopathologi- mild and common to many agents (Correas et al. cal evidence of myocardial damage. Furthermore, 2001). Allergy-like reactions occur rarely; general in one study on rats, several types of arrhythmia flush with erythema and papules has been reported were observed when ultrasound contrast media and (Correas et al. 2001). Three anaphylactic reactions ultrasound were combined (Zachary et al. 2002). have been reported, two in women aged 59 and 70 Disruption of the blood–brain barrier may occur years respectively, and one in a man of 70 years (de in rats after intravenous injection of ultrasound Groot et al. 2004). Asymptomatic premature ven- contrast media (Mychaskiw et al. 2000). tricular contractions have been observed during The combination of ultrasound exposure and triggered imaging with ultrasound contrast (van ultrasound contrast media may cause damage to der Vouw et al. 2000). the endothelial cells and venules and capillar- It has been recommended that therapeutic ultra- ies in rat mesentery (Kobayashi et al. 2002, 2003; sound and lithotripsy should be avoided in the day Rasmussen et al. 2003). following the use of ultrasound contrast agents Safety of Ultrasound Contrast Agents 133

(Brayman and Miller 1997; Dalecki et al. 1997; 19.5 Delius 1994). Decisions about the use of contrast Recommendation on the Use of Ultrasound materials in the maternal circulation depend on the Contrast Media clinical condition of the mother (Rott 1999, Ecmus (2004). The European Committee for Medical Ultrasound European Medicine Agency (EMMA) recently took Safety (ECMUS) recommends that ultrasound con- precautionary measures to limit the use of the ultra- trast media should only be used if there is a good sonographic contrast agent sulphur hexafluoride in clinical indication, and the risk/benefit ratio should patients with cardiac disease. Throughout Europe a be carefully assessed (ECMUS 2004). In addition number of serious allergic reactions with probable sec- this Committee emphasized that high values of ondary cardiovascular problems have been reported. Mechanical Index should be used only when essen- In addition to this, there have been three reports of tial for a particular clinical study (ECMUS 2003). fatal outcome soon after the administration of this It is important to acknowledge that ultrasound agent. All of these patients were however at risk of contrast media are fairly new products and it may serious cardiac complications because of underlying take several years of accurate surveillance to docu- cardiac problems (de Groot et al. 2004) (Table 19.2). ment possible adverse reactions to them. It is also not clear whether there are important differences in safety among the products currently available. Table 19.2. Frequency of adverse reactions during intravenous administration ultrasound contrast agents (for manufacturer details, see Table 19.1)

Product name Adverse reaction Adverse reaction <1% 19.6 Reported 0.5%–5% Reported <1% Conclusion Levovist, Body as a whole Body as a whole Optison, Headache Abdominal pain In vitro and animal studies have shown adverse SonoVue Hypersensitivity at Weakness injection site Pain effects of ultrasound contrast media related to Back pain the properties of the particles and the interaction Chest pain between microbubbles and ultrasound beam energy Fatigue causing bubble destruction. However, clinical stud- Cardiovascular Cardiovascular ies have not shown such adverse events and indicate system system that ultrasound contrast media are generally safe. Hypertension Atrial fibrillation Most adverse events seen clinically are non-spe- Palpitation Tachycardia cific and unrelated to the constituents of the various products. Adverse reactions are usually minor Digestive system Digestive system Nausea Anorexia (e.g., headache, nausea, altered taste, sensation of Diarrhea heat) and self resolving. These symptoms may not Dyspepsia be related to the ultrasound contrast materials as Musculoskeletal system they have also been observed in placebo-control- Leg cramps led groups. Intolerance to some components may Nervous system Nervous system occur. Generalized allergy-like or hypersensitivity Dizziness Paresthesia reactions occur only rarely. Any rare adverse reac- Dry mouth Vasodilatation tions should be treated symptomatically. Special senses Respiratory system The use of ultrasound contrast media should Abnormal smell or Dyspnoea always be clinically justified. It is important that taste the exposure time to ultrasound and the acoustic Skin and appendages output shown be kept to lowest level consistent with Sweating obtaining diagnostic information. A guideline on Rash the safety of ultrasound contrast media can been Pruritus found in the Appendix. 134 R. Oyen

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